HIV-1 Protease Dimerization Dynamics Reveals a Transient Druggable Binding Pocket at the Interface

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• HIV-1 protease is essential for viral replication and exists as an inactive monomer, requiring dimerization to become catalytically active.
• Understanding the monomer-dimer association mechanism is crucial for developing effective HIV-1 protease inhibitors.

Purpose of the Study:

• To investigate the binding mechanism of HIV-1 protease monomers using advanced computational simulations.
• To identify potential new drug targets within the dimerization interface.

Main Methods:

• State-of-the-art atomistic simulations were employed to model the dimerization process.
• Molecular mechanics with generalized Born surface area (MM-GBSA) calculations and molecular docking were used to assess binding affinities and druggability.

Main Results:

• Water molecules at the interface significantly influence and slow down the association kinetics of protease monomers.
• A novel, transient cryptic binding pocket was discovered at the interface of a partially bound, inactive dimer.
• This pocket exhibits favorable druggability characteristics and a lifetime exceeding 1 μs.

Conclusions:

• The findings provide a deeper mechanistic understanding of HIV-1 protease dimerization and the role of interfacial water.
• The identified cryptic binding pocket represents a promising new target for developing novel anti-HIV therapeutics.
• Inhibitors targeting this pocket could prevent complete dimerization, yielding a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs).